CN107735167A - Blood treatment seperation film and group enter the blood processor of the film - Google Patents
Blood treatment seperation film and group enter the blood processor of the film Download PDFInfo
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- CN107735167A CN107735167A CN201680036377.XA CN201680036377A CN107735167A CN 107735167 A CN107735167 A CN 107735167A CN 201680036377 A CN201680036377 A CN 201680036377A CN 107735167 A CN107735167 A CN 107735167A
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- blood
- seperation film
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- 238000001226 reprecipitation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- SBIBMFFZSBJNJF-UHFFFAOYSA-N selenium;zinc Chemical compound [Se]=[Zn] SBIBMFFZSBJNJF-UHFFFAOYSA-N 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0002—Organic membrane manufacture
- B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
- B01D67/0011—Casting solutions therefor
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01D67/0002—Organic membrane manufacture
- B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
- B01D67/0011—Casting solutions therefor
- B01D67/00111—Polymer pretreatment in the casting solutions
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- B01D67/0081—After-treatment of organic or inorganic membranes
- B01D67/0088—Physical treatment with compounds, e.g. swelling, coating or impregnation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01D69/087—Details relating to the spinning process
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- B01D71/06—Organic material
- B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
- B01D71/401—Polymers based on the polymerisation of acrylic acid, e.g. polyacrylate
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- B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
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- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
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- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/04—Coating
- C08J7/043—Improving the adhesiveness of the coatings per se, e.g. forming primers
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L39/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions of derivatives of such polymers
- C08L39/04—Homopolymers or copolymers of monomers containing heterocyclic rings having nitrogen as ring member
- C08L39/06—Homopolymers or copolymers of N-vinyl-pyrrolidones
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L81/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing sulfur with or without nitrogen, oxygen or carbon only; Compositions of polysulfones; Compositions of derivatives of such polymers
- C08L81/06—Polysulfones; Polyethersulfones
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- C08J2433/14—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters of esters containing halogen, nitrogen, sulfur, or oxygen atoms in addition to the carboxy oxygen
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Abstract
A kind of blood treatment seperation film, it has：Seperation film containing polysulfones system macromolecule and PVP；With at least a portion on the surface that is arranged at the seperation film and comprising with the high polymer material of structure shown in following formulas (1) overlay film [in formula, R1It is hydrogen atom or methyl, R2It is methyl or ethyl, n is that 2~6, m is that 1~3, P represents repeat number, multiple R in a molecule1、R2, n and m each can be the same or different.]
Description
Technical field
The present invention relates in order to by the predetermined substance separation in blood, exclude and the blood treatment seperation film that uses and
Group enters the blood processor of the film.
Background technology
In extracorporal circulatory system therapy, used the hollow fiber membrane-type blood processor of the seperation film of selectivity is made extensively
With.Such as in the haemodialysis for the maintenance therapy of patients of chronic renal failure, declined as acute renal
Exhaust, the filtering of the sustained blood of the acute blood purification therapy of the patient of serious illness such as septicemia, sustained blood filtering dialysis, hold
In continuous haemodialysis etc., in addition, the oxygen to blood in open heart operation assign or blood plasma separation etc. in, use hollow fiber membrane-type
Blood processor.
In these purposes, as seperation film, it is desirable to mechanical intensity, chemical excellent in stability, do not require nothing more than in addition
Cross that the control of performance is easy, also require leachable it is few, with the interaction of biological component less, be safe for organism.
In recent years, from the viewpoint of the intensity from machinery, the stability of chemistry, diactinic controlling, by polysulfones system tree
The seperation film that fat is formed rapidly is popularized.Because polysulfones system resin is hydrophobic polymer, therefore as former state in use, the parent on film surface
It is water-based it is significantly insufficient, blood compatibility is poor, cause interaction with blood constituent, also easily produce solidification of blood etc.,
And then due to protein ingredient etc. absorption and through performance easily deteriorates.
Therefore, in order to make up these shortcomings, study in addition to the hydrophobic polymers such as polysulfones system resin, also containing poly- second
The hydrophilic macromolecules such as vinyl pyrrolidone (PVP), polyvinyl alcohol, polyethylene glycol, thus assign blood compatibility.It is such as known
The spinning solution formed by using hydrophobic polymer and hydrophilic macromolecule blending is film-made and is dried, and is made manufactured
Film contacted with the solution containing hydrophilic macromolecule after be dried, thus with hydrophilic macromolecule cover seperation film, assign
Method of blood compatibility etc..
And in extracorporal circulatory system therapy, the seperation film in blood processor directly contacts blood to use, it is therefore desirable to makes
Sterilization treatment is carried out to seperation film with preceding.
In sterilization treatment, using ethylene oxide gas, high pressure steam, radiation etc., but gone out using ethylene oxide gas
When bacterium, autoclaving, allergy caused by residual gas, the disposal ability of bactericidal unit, material be present
The problems such as thermal deformation, present gamma-rays, the sterilizing of electron beam israds turn into main flow.
But from operability, cold district keeping when freezing the problem of etc. consider, as blood processor, dry products
Have become in main flow, when carrying out radiation sterilizing in the presence of oxygen, hydrophilic macromolecule is produced due to producing free radical
Cross-linking reaction, decomposition and then oxidative degradation etc., thus cause denaturation in film raw material, turn into the reason for blood compatibility reduces.
As the method for preventing this seperation film deterioration caused by radioactivity sterilizes, for being not dry products
Product, disclose by filling antioxidant solution to membrane module, carrying out γ ray sterilization, thus prevent the oxidative degradation of film
Method (patent document 1), by filling PH buffer solutions, aqueous alkali, sterilized, thus suppress the method for the oxidation of filling liquid
(patent document 2).
On the other hand, for dry products, disclose and suppress oxygen concentration when sterilizing in more than 0.001% and 0.1%
Following method (patent document 3).But, it is necessary to will be put in packaging bag with non-active gas in the technology of patent document 3
Bring and sterilized or deoxidier is enclosed into packaging bag, is sterilized etc. after certain time, fundamentally solve drying
Under state and air radiation sterilize caused by the seperation film containing hydrophilic macromolecule deterioration the problem of skill
Art is not established.
In addition, in order to improve blood compatibility, it is proposed that be coated with blood compatible polymer in hollow fiber separating film.
But according to the species for the polymer for forming seperation film, application conditions, the fine hole plug due to coating thickness
Deng, exist as the function of hollow fiber separating film it is hindered the problems such as.
Such as recorded in patent document 4,5, coated comprising polyacrylic hollow fiber membrane surface with rated condition
PMEA (polyacrylic acid methoxy acrylate), but because coating is uneven, blood compatibility produces deviation, and therefore, it is difficult to say stably
Obtain the film with high blood compatibility.Therefore, seek not coating inequality in blood treatment field, equably there is height
Blood compatibility film.
And then Patent Document 6 discloses the high score with the structure identical structure shown in the formula (1) with the application
Sub- material.
But for the seperation film containing polysulfones system macromolecule and PVP in these documents, it is right in addition
In sterilization treatment all without disclosure, enter accordingly, with respect to the seperation film containing polysulfones system macromolecule and PVP
The deterioration of seperation film during row sterilization treatment, blood compatibility are reduced and not recorded.
Prior art literature
Patent document
Patent document 1：Japanese Unexamined Patent Publication 4-338223 publications
Patent document 2：Japanese Unexamined Patent Publication 7-194949 publications
Patent document 3：International Publication No. 2006/016575
Patent document 4：No. 3908839 publications of Japan Patent
Patent document 5：Japanese Unexamined Patent Publication 2015-136383 publications
Patent document 6：No. 4746984 publications of Japan Patent
The content of the invention
Problems to be solved by the invention
It is an object of the present invention to provide separation function, blood compatibility are excellent, under air, under drying regime
It is also few to carry out radiation sterilizing, the reduction of blood compatibility, blood compatibility reduction will not be also produced even across long-term use
Blood treatment seperation film and group enter the blood processor of the film, particularly purpose is, by for base material (separation
Film) technical characteristic of coating blood compatible polymer realizes this blood treatment seperation film.
The solution used to solve the problem
The present inventor etc. are furtherd investigate to solve the above problems, and are as a result found, are coated with conventional blood phase
One of the reasons why blood compatibility of the blood treatment seperation film of capacitive polymer is insufficient think to be, hollow-fibre membrane with
Cementability between blood compatible polymer overlay film is bad, due to coating is uneven and a part for the overlay film of seperation film not by
Immobilization.
And it was found that it is coated with the seperation film at least containing polysulfones system macromolecule and PVP comprising tool
There is the blood treatment seperation film of the overlay film of the high polymer material of structure shown in following formulas (1), there is very excellent blood
Compatibility, sterilized the blood compatibility for also maintaining it very excellent under air, and then between seperation film and overlay film
Cementability is also good, film use when overlay film will not peel off, the reduction of blood compatibility is lacked, so as to complete the present invention.
In formula, R1It is hydrogen atom or methyl, R2It is methyl or ethyl, n is that 2~6, m is that 1~3, P represents repeat number, one point
Multiple R in son1、R2, n and m each can be the same or different.
That is, the present invention as described below.
[1] a kind of blood treatment seperation film, it has：
Seperation film containing polysulfones system macromolecule and PVP；With
It is arranged at least a portion on the surface of the seperation film and comprising the high score with structure shown in following formulas (1)
The overlay film of sub- material,
In formula (1), R1It is hydrogen atom or methyl, R2It is methyl or ethyl, n is that 2~6, m is that 1~3, P represents repeat number,
Multiple R in one molecule1、R2, n and m each can be the same or different.
[2] according to the blood treatment seperation film described in [1], wherein, the macromolecule with structure shown in aforementioned formula (1)
The number-average molecular weight of material is 8000~300000.
[3] the blood treatment seperation film according to [1] or [2], wherein, ATR-FTIR absorption is being implemented to surface
In infrared absorption curve when determining (ATR-IR), 1735cm-1The peak intensity P1 and 1595cm of neighbouring infrared absorption peak-1's
The ratio between the peak intensity P2 of infrared absorption peak P1/P2 is more than 0.015.
[4] the blood treatment seperation film according to any one of [1]~[3], wherein, R in formula (1)1It is hydrogen original
Son, R2It is that ethyl, n are that 2, m is 2.
[5] the blood treatment seperation film according to any one of [1]~[3], wherein, R in formula (1)1Be methyl,
R2It is that methyl, n are that 2, m is 2.
[6] the blood treatment seperation film according to any one of [1]~[3], wherein, R in formula (1)1Be methyl,
R2It is that ethyl, n are that 2, m is 2.
[7] the blood treatment seperation film according to any one of [1]~[3], wherein, R in formula (1)1It is hydrogen original
Son, R2It is that methyl, n are that 3, m is 1.
[8] the blood treatment seperation film according to any one of [1]~[3], wherein, R in formula (1)1It is hydrogen original
Son, R2It is that methyl, n are that 4, m is 1.
[9] the blood treatment seperation film according to any one of [1]~[3], wherein, R in formula (1)1It is hydrogen original
Son, R2It is that methyl, n are that 5, m is 1.
[10] the blood treatment seperation film according to any one of [1]~[3], wherein, R in formula (1)1It is hydrogen original
Son, R2It is that methyl, n are that 6, m is 1.
[11] a kind of blood processor, it includes the blood treatment seperation film any one of [1]~[10].
[12] a kind of manufacture method of blood treatment seperation film, it has：
The process for manufacturing the seperation film containing polysulfones system macromolecule and PVP；With
At least a portion coating on the surface of aforementioned separation membrane contains the high polymer material with structure shown in formula (1)
Coating fluid process.
[13] according to the manufacture method of the blood treatment seperation film described in [12], wherein, aforementioned coating liquid contain water and
Organic solvent, aforementioned organic solvents are ethanol, methanol or its mixture.
[14] manufacture method of the blood treatment seperation film according to [12] or [13], wherein,
In the process of manufacture aforementioned separation membrane,
Seperation film uses to be film-made containing the film stoste of polysulfones system macromolecule and PVP, the film stoste
In PVP be relative to the high molecular ratio of polysulfones system (PVP/polysulfones system macromolecule)
Below 27 mass %.
[15] a kind of manufacture method of blood processor, its be [11] described in blood processor manufacture method, its according to
It is secondary to have：
The process for manufacturing the seperation film containing polysulfones system macromolecule and PVP；
The process being packaged to seal the inner space of aforementioned separation membrane and outer space；With
Contain the macromolecule with structure shown in formula (1) on the surface of aforementioned separation membrane and the coating of the surface of aforementioned encapsulation
The process of the coating fluid of material.
The effect of invention
The blood treatment seperation film and group of the present invention has entered the blood processor of the film, under air, dries shape
In the case that state carries out radiation sterilizing, very excellent blood compatibility can also be shown.
In addition, for the present invention blood treatment seperation film, between seperation film and blood compatible polymer overlay film
Cementability is good, it is taken as that also without it is long-term use of when blood compatibility reduce the problems such as.
And then the blood processor of the film is entered according to the blood treatment seperation film and group of the present invention, even for due to
Infectious disease etc. and produce the organism of inflammation blood handled in the case of, attachment of the cohesive protein to seperation film
It is few, it will not bring obstacle in treatment.
Also, in the blood treatment seperation film of the present invention, due to can be with thin and equably polymerize blood compatibility
Thing is coated in seperation film, therefore the coating of necessity and sufficiency can be carried out with a small amount of blood compatible polymer.
Brief description of the drawings
Fig. 1 is the blood treatment separation membrane surface implementation ATR-FTIR absorption measurement (ATR-IR) for embodiment 1
When infrared absorption curve.
Fig. 2 is to implement thermal cracking gas chromatography matter for poly- [acrylic acid 2- (2- ethoxy ethoxies) ethyl ester] (PEt2A)
Chromatogram during spectrum analysis.
The blood treatment seperation film implementation thermal cracking gas chromatography mass spectral analysis of chromatogram when Fig. 3 is to(for) embodiment 1
Figure.
Fig. 4 is the mass spectrum at the neighbouring peaks of chromatogram RT7.9 (minute) of the blood treatment seperation film of embodiment 1.Need
It is bright, it is parsed, is as a result accredited as the chemical structural formula (2- (2- ethoxy ethoxies) ethanol) shown in bottom.
Fig. 5 is the mass spectrum at the neighbouring peaks of chromatogram RT12.7 (minute) of the blood treatment seperation film of embodiment 9.Need
It is bright, it is parsed, is as a result accredited as chemical structural formula (methacrylic acid 2- (the 2- methoxyl group ethoxies shown in bottom
Base) ethyl ester).
Fig. 6 is the blood treatment separation membrane surface for being coated with for embodiment 11 poly- [acrylic acid 3- methoxyl groups propyl ester]
Implement infrared absorption curve during ATR-FTIR absorption measurement (ATR-IR).
Fig. 7 is chromatogram when implementing thermal cracking gas chromatography mass spectral analysis for poly- [acrylic acid 3- methoxyl groups propyl ester].
Fig. 8 is implemented for the blood treatment for being coated with for embodiment 11 poly- [acrylic acid 3- methoxyl groups propyl ester] with seperation film
Chromatogram during thermal cracking gas chromatography mass spectral analysis.
Fig. 9 is the mass spectrum at the neighbouring peaks of chromatogram RT3.2 (minute) of poly- [the acrylic acid 3- methoxyl groups propyl ester] of embodiment 11.
It should be noted that being parsed to it, the chemical structural formula trimethylene monomethyl ether shown in bottom is as a result accredited as.
Figure 10 be represent embodiment 22 in used inflammatory model blood blood compatibility evaluate after hollow fibre
Tie up the photo of the surface state of seperation film (coating PMC3A).
Figure 11 be represent embodiment 22 in used inflammatory model blood blood compatibility evaluate after hollow fibre
Tie up the photo of the surface state of seperation film (coating PEt2A).
Figure 12 be represent comparative example 5 in used inflammatory model blood blood compatibility evaluate after doughnut
The photo of the surface state of seperation film (not being coated with).
Embodiment
It is described in detail below for the mode (hereinafter referred to as " present embodiment ") for implementing the present invention.Need
Bright, the present invention is not limited by following embodiment, and various modifications can be carried out to implement in the range of its purport.
The blood treatment of present embodiment is included containing polysulfones system macromolecule and PVP with seperation film
Seperation film, the surface of the seperation film at least a portion with for assign blood compatibility include with aforementioned formula
(1) overlay film of the high polymer material (being only called sometimes below " high polymer material of formula (1) ") of structure shown in.
Illustrated firstly for the seperation film containing polysulfones system macromolecule and PVP.
<Polysulfones system macromolecule>
In present embodiment, polysulfones system macromolecule refers to containing sulfuryl (- SO in its structure2-) macromolecule.As
The concrete example of polysulfones system resin, PPSU, polysulfones, polyallyl ether sulfone, polyether sulfone and their copolymer etc. can be included.
As polysulfones system macromolecule, it can be used alone, two or more mixtures can also be used in addition.
Wherein, from the viewpoint of control fractionation property, the polysulfones system preferably shown in following formula (a) or following formula (b) is high
Molecule.
(-Ar-SO2-Ar-O-Ar-C(CH3)2-Ar-O-)n (a)
(-Ar-SO2-Ar-O-)n (b)
In formula (a) and formula (b), Ar represents phenyl ring, and n represents the repetition of polymer, the integer for being more than 1.
As the polysulfones system macromolecule shown in formula (a), can include for example by Solvay S.A. with " Udel (trade mark) "
The commercially available product of title, by BASF SE with the commercially available product of the title of " Ultra Zone (trade mark) ".In addition, as shown in formula (b)
Polyether sulfone, it can include for example by Sumitomo Chemical Co with the commercially available product of the title of " Sumica Exel (trade mark) ", according to
Degree of polymerization etc. and several species be present, therefore can suitably utilize them.
<PVP>
PVP refer to by NVP progress vinyl polymerization form it is water miscible
Hydrophilic macromolecule, as hydrophilic agent, pore-forming agent, it is widely used as the raw material of hollow-fibre membrane.
It is commercially available several with the title difference of " Luvitec (trade mark) " as PVP, such as by BASF SE
The commercially available product of molecular weight, therefore can suitably utilize them.
It as PVP, can be used alone, two or more mixtures can also be used in addition.
In present embodiment, by making seperation film contain PVP, contain the macromolecule shown in formula (1)
The overlay film of material and the adhesive strength of seperation film improve, it is thus regarded that the drop of blood compatibility when can prevent long-term use
It is low.
Seperation film can also contain the structure beyond polysulfones system macromolecule and PVP as its constituent
Into composition.As other constituents, such as polymethylacrylic acid hydroxy methacrylate, polymethylacrylic acid hydroxyl third can be included
Polymethylacrylic acid hydroxyalkyl acrylate, the polyethylene glycol such as ester, polymethylacrylic acid hydroxybutyl.For containing for other constituents
Amount does not limit, and can be below 20 mass %, can also be below 10 mass %, can also be below 5 mass %.In addition,
Other constituents can also be entirely free of.
In addition, in the seperation film of present embodiment, if PVP is relative to the high molecular ratio of polysulfones system
Be set to below 42 mass % then due to can suppress the stripping quantity of PVP and it is preferred that, more preferably 27 mass % with
Under.
On the other hand, examined from the viewpoint of the overlay film comprising the high polymer material shown in formula (1) and the cementability of seperation film
Consider, PVP is preferably more than 15 mass % relative to the high molecular ratio of polysulfones system, more preferably 20 mass %
More than, the PVP concentration of separation membrane surface can be then controlled in suitably if more than 18 mass % in addition
In the range of, the effect for suppressing protein absorption is improved, the excellent blood treatment seperation film of blood compatibility can be formed.
Do not limited for the shape of seperation film, it is preferred that seperation film has hollow fibre shape.In addition, from permeability
From the viewpoint of energy, curling is further preferably assigned.
Illustrated sequentially for the overlay film of the high polymer material comprising formula (1).
For the high polymer material of formula (1), due to the ehter bond, the polar group of ester bond and biology that contain in molecular structure
Body composition does not have in strong electrostatic interaction and molecular structure and does not have big hydrophobic group, therefore even if blood
Contact will not also produce the activation in blood, be so-called blood compatibility material.
The part that the high polymer material of formula (1) is particularly the side chain shown in following formulas (1) has feature.
[in formula, R1It is hydrogen atom or methyl, R2It is methyl or ethyl, n is that 2~6, m is that 1~3, P represents repeat number, one point
Multiple R in son1、R2, n and m each can be the same or different.]
The transport properties of molecules of the side chain of said structure is high, it is taken as that the Tg of the high polymer material with this side chain it is small or
Person produces distinctive effect in the present invention.
That is, the high polymer material of formula (1) due to the transport properties of molecules of side chain it is high, therefore on the surface of the overlay film containing it
In, the contact with main chain such as biological component contained in processing blood is not likely to produce, its result thinks biocompatible liter
Height, cohesive protein, hematoblastic absorption denaturation become slight.
The high polymer material of formula (1) can shown in formula (1) in the range of include it is a variety of with different structure
Side chain.And then the high polymer material of formula (1) includes the structure (repeat unit) shown in formula (1), therefore, if being in
Do not depart from the range of present inventive concept then such as can include with the unit of n=1 side-chain structure in formula (1).But
It is that the construction unit of the high polymer material of formula (1) is more preferably at least acrylic acid, methacrylic acid or their derivative.
In the high polymer material of formula (1), if being led relative to the carbon atom 10 of composition main chain, with the ratio of 1 or so
Enter the side chain of the structure shown in formula (1), then can show the various features due to the side chain, with formula (1)
The density of shown side chain raises and more strongly shows these features.Particularly main chain is the situation (R of acrylic backbone1
For the situation of hydrogen atom) under, side chain is imported with the ratio of 1 relative to the carbon atom 2 for forming main chain, can consumingly be showed
Go out the feature due to side chain.
Therefore, in the high polymer material of formula (1), relative to the carbon atom 10 for forming main chain, formula (1) is preferably comprised
Shown in side chain more than 1, further preferably more than 2, further preferably more than 5.
High polymer material containing structure shown in formula (1) is the polymer containing middle water, is merely deposited in the structure
In ester bond, ehter bond, it is taken as that not only blood compatibility is good, and the state of the middle water on its surface is adsorbed in for blood
Compatibility causes big influence.And the side chain shown in formula (1), in the case where n value is 2~4, the content of middle water
Height, therefore the high polymer material that formula (1) be present is aqueous and is not easy the tendency of adsorbed proteins etc..On the other hand, it is in n value
In the case of 5~6, while the high polymer material of formula (1) maintains biocompatible, the protein in aqueous solution is showed
The special property such as adsorb with will not being denatured.
In addition, defined characteristic is shown in wide temperature range when above-mentioned m value is 1, and when m value is 2,3, side chain
It is elongated, the change increase of thus molecular motion, it is possible to by boundary line of specific temperature there is the solubility in water drastically to become
The lower limit critical consolute temperature (LCST) of change, upper critical consolute temperature (UCST) etc..
If in addition, R1For hydrogen, then high polymer material goes out high hydrophily as general performance, if R1Then produced for methyl hydrophobic
Change, for being effective for assigning resistance to water solubility to seperation film.
In the high polymer material of formula (1) part as biocompatible polymer, it is known that distinguish by containing its
Overlay film shows especially excellent blood compatibility in the case of being arranged at the surface of the seperation film containing PVP
Property.
And then distinguish, the high polymer material of formula (1) also shows good even for the blood of the organism of inflammatory conditions
Good compatibility.
That is, in the case that organism produces inflammation due to infectious disease etc., endothelial cell activation or by obstacle
And while the protein increase of the cohesive in blood, blood clotting X II is factors activated, therefore blood easily solidifies.
Therefore, when this blood contacts with seperation film, the protein attachment of cohesive frequently produces residual blood (blood in separation membrane surface
Solidification is adhered to the phenomenon of seperation film).As a result, during dialysis, it is absorbed in and produces dialytic efficiency reduction or dialysis treatment until most
Can not terminate untill afterwards, can not realize blood in dialysis circuit return the very serious situations such as the bad problem such as blood.
But even for the blood for the inflammatory conditions for causing this Yan Chong Zhuan Condition, the high polymer material of formula (1) also table
Reveal good compatibility, it is believed that during using the seperation film on surface with it, the adsorbance of cohesive protein is few or locates
In the state being also easily peeled off even if protein absorption, above-mentioned bad problem is not likely to produce.
It will also realize that there is the blood compatibility of seperation film of the high polymer material of formula (1) on surface in top layer in addition
Its amount it is more in the case of, improve tremendously.
Seperation film containing polysulfones system macromolecule and PVP is porous body, if therefore being applied in coating thereon
Then coating fluid is infiltrated up in seperation film cloth liquid possibly through hole.In particular according to the solvent of coating fluid species and seperation film
Aperture be also possible to increase, in this case, further easily produce infiltration.
In addition, according to the species of the solvent of coating fluid, by coating solution when in seperation film, there is also flowed by its surface
Go out, can not be in many situations of superficial residence.
So think, the species and group of the solvent of the coating fluid of the high polymer material containing formula (1) used during coating
The amount on the top layer for existing in seperation film after coating into the high polymer material of, the formula (1) for being coated in seperation film is made
Into influence.
That is, the coating solution of the high polymer material dissolved with formula (1), is preferably being coated on the table of porous seperation film
When on face, surface is still stayed in and the high polymer material of formula (1) stays in the coating solution on surface.
And the present inventor etc. is furtherd investigate, as a result understand, the solvent of coating fluid is water and the mixture of organic solvent
In the case of, amount significantly change of the high polymer material of formula (1) in superficial residence according to the mixing ratio of water and organic solvent.
Specifically, have that the blending ratio of organic solvent is smaller, the high polymer material of formula (1) more easily stays in
The tendency of separation membrane surface.Its reason is indefinite, but presumption is due to, in the high score of the solvent dissolving formula (1) of coating fluid
In the range of sub- material, the high polymer material of formula (1) dissolves well if the blending ratio of the organic solvent in solvent is big
In coating fluid, therefore by coating solution when in seperation film, the high polymer material of formula (1) is also infiltrated up in film, it is difficult to is stopped
Stay in surface, and the high polymer material of formula (1) is small for the solubility of coating fluid if the blending ratio of organic solvent is small, because
If by coating solution when in seperation film, organic solvent is infiltrated up to first to be waited in film and organic solvent/water in solvent for this
Balance is destroyed, then the high polymer material of formula (1) is separated out by coating fluid, residued on separation membrane surface.
Although the blending ratio of organic solvent when the solvent of coating fluid is the mixture of water and organic solvent also depends on
The species of the high polymer material of formula (1), but in the limit of the high polymer material in dissolving formula (1), preferably 80 matter
Measure below %, more preferably below 60 mass %, further preferred below 40 mass %.
In addition, it is known that in ATR-IR methods, the ripple for inciding sample reflects due to creeping on a small quantity to sample, therefore can survey
The infrared absorption in the fixed drilling depth region, the as a result discovery such as the present inventor, the mensuration region of the ATR-IR methods and foregoing " table
The depth of layer " is roughly equal.That is, the blood compatibility in the depth areas roughly equal with the mensuration region of ATR-IR methods dominates
The blood compatibility of the sample (blood treatment seperation film), it is contemplated that by the high polymer material of formula (1) in the region be present
More than specified quantitative (that is, using the macromolecule material from formula (1) in the infrared absorption curve obtained using ATR-IR
The peak intensity of material carrys out the amount of the high polymer material of regulation formula (1)), it can provide at the blood with certain blood compatibility
Reason seperation film, so as to complete the preferred mode of the present invention.
It should be noted that the wavelength of the infrared light depended on using the mensuration region of ATR-IR methods in air, incidence angle,
The refractive index of prism, refractive index of sample etc., the usually region from film surface within 1 μm.
The high polymer material of formula (1) is present in separation membrane surface, can pass through the thermal cracking gas chromatography matter of seperation film
Spectrum is analyzed to confirm.Presence for the high polymer material of formula (1), if the ATR-FTIR on the surface for seperation film is inhaled
Receive in (ATR-IR) measure, in the 1735cm of infrared absorption curve-1Nearby find that peak is then estimated, but the neighbouring peak
It is possible to be derived from other materials.
Therefore thermal cracking gas chromatography mass spectral analysis is carried out, the lysate of the high polymer material of formula (1) is confirmed, thus may be used
To conclude that the high polymer material of formula (1) is present in surface.
In order to which the blood treatment in present embodiment shows sufficient blood compatibility in practicality with seperation film, utilize
Ester group-the O-C=O of the high polymer material from formula (1) of ATR-IR measure infrared absorption peak (1735cm-1Near) peak
Intensity P1 is relative to the infrared absorption peak (1595cm from the high molecular C=C of polysulfones system (C=C in Ar)-1Near) peak intensity
It is preferably more than 0.015, more preferably more than 0.02, further preferred more than 0.03 to spend the ratio between P2 (P1/P2), still more preferably
More than 0.04, particularly preferred more than 0.05.
The reasons why blood compatibility of the blood treatment seperation film of present embodiment is very excellent is indefinite, but estimates
Produced between the high polymer material for being due to PVP (PVP) and the formula (1) contained in seperation film some
Interact (such as mutual winding between the molecule between the high polymer material of PVP and formula (1)).
In addition, the overlay film for also having the high polymer material containing formula (1) if seperation film contains PVP is more firmly consolidated
Due to the effect in seperation film.Estimate what this was realized also with above-mentioned interaction.
Peak (the 1735cm of the foregoing high polymer material from formula (1)-1Near) with being derived from the high molecular peak of polysulfones system
(1595cm-1Near) peak intensity ratio (P1/P2), the composition of the solvent of the coating fluid used when can be by making coating is (specific
For, the mixing ratio of organic solvent and water) change to adjust.Specifically, when the amount of organic solvent more at most implements ATR-IR
The high polymer material from formula (1) peak (1735cm-1Near) peak intensity P1 it is weaker, organic solvent amount is derived from more at least
Peak (the 1735cm of the high polymer material of formula (1)-1Near) peak intensity P1 it is stronger.
The high polymer material of formula (1) has specificity for the dissolubility of solvent.Such as poly- [acrylic acid 2- (2- ethoxies
Base oxethyl) ethyl ester], in the case of poly- [acrylic acid 3- methoxyl groups propyl ester], it is different for the dissolubility of 100% ethanol, still
The region dissolved according to its mixing ratio in water/alcohol mixed solvent all be present.And for the mixing in the region of the dissolving
Than for, to form coating then poly- [acrylic acid 2- (2- ethoxy ethoxies) ethyl ester] and poly- [acrylic acid 3- water more
Methoxyl group propyl ester] peak (1735cm-1Near) peak intensity P1 become stronger.
For being for example coated with containing poly- [third in the separation membrane surface containing polysulfones system macromolecule and PVP
Olefin(e) acid 2- (2- ethoxy ethoxies) ethyl ester], the overlay film of poly- [acrylic acid 3- methoxyl groups propyl ester] when contain poly- [acrylic acid 2-
(2- ethoxy ethoxies) ethyl ester], existence of the overlay film of poly- [acrylic acid 3- methoxyl groups propyl ester] in seperation film, Ke Yitong
Measure is crossed as the UFR of one of water permeability index to evaluate.
Applied with the overlay film containing poly- [acrylic acid 2- (2- ethoxy ethoxies) ethyl ester], poly- [acrylic acid 3- methoxyl groups propyl ester]
In the case of cloth seperation film, the change in the aperture of the porous film surface is small, therefore water permeability less changes, product design letter
It is single.It is thought that due to containing poly- [acrylic acid 2- (2- ethoxy ethoxies) ethyl ester], poly- [acrylic acid 3- methoxyl groups propyl ester]
Overlay film with it is very thin it is membranaceous be attached to separation membrane surface, seperation film is coated with the state of less plugging hole.
In present embodiment, the number-average molecular weight of the high polymer material of formula (1) is preferably 8000~300000.If number is equal
Molecular weight is that less than 8000 then being wound with mutually between molecule may be insufficient, there is that leachable is increased to incline when forming product
To then operating easy degree (cohesive and hardness) if more than 300000 in addition and the dissolubility of solvent be deteriorated, find not
The tendency that can fully dissolve.Number-average molecular weight is more preferably 10000~250000, further preferred 10000~200000.
In present embodiment, the number-average molecular weight of the high polymer material of formula (1) is for example as described in embodiment, Ke Yitong
Cross the measure such as gel permeation chromatography (GPC).
In present embodiment, the side as the overlay film that the high polymer material containing formula (1) is set on the surface of seperation film
Method, such as suitably use film (spinning) stoste by the high polymer material mixed dissolution of formula (1) when seperation film is film-made
And carry out the method for spinning, by hollow interior liquid of the high polymer material mixed dissolution of formula (1) when seperation film is film-made and carry out
The method of spinning and will be dissolved with formula (1) high polymer material coating liquid in method of seperation film etc..
Among these methods, if considering dissolving of the high polymer material of formula (1) for film stoste and hollow interior liquid
Property, then it is assumed that it is most suitable that the painting method of coating fluid is coated in seperation film.
Coating liquid as the high polymer material that will be dissolved with formula (1), can be for dividing in the method for seperation film
From film, suitably seperation film is film-made and after group enters to blood processor to be molded, circulated coating fluid for separation membrane surface
Contacted, thus covered.
The overlay film of high polymer material containing formula (1) is arranged at least a portion on the surface of seperation film.Contain
The overlay film of the high polymer material of formula (1) is preferably disposed on all surfaces of seperation film, but on the other hand, it is also possible to it is difficult to
Formed as continuous film.Therefore, the overlay film of the high polymer material containing formula (1) is preferably at least dispersed throughout whole tables of seperation film
Face is set.
The blood treatment seperation film of present embodiment can also for example lead under the atmosphere of oxygen concentration more than 15%
The sterilizing of overshoot line carries out sterilization treatment.That is, when implementing radiation sterilizing with seperation film for blood treatment, without using deoxidation
Agent is replaced into the non-active gas such as nitrogen and reduces oxygen concentration, can implement radiation sterilizing under air.
Illustrated sequentially for blood processor.
The blood processor of present embodiment is the blood treatment for the blood treatment seperation film that group enters to have present embodiment
Device, it can be used for the bodies such as haemodialysis, blood filtration, blood filtration dialysis, blood constituent fractionation, imparting oxygen and blood plasma separation
The blood purification therapy of outer circulation type.For the blood processor of present embodiment, even for its blood treatment seperation film
In the case of implementing radiation sterilizing under air, the PVP and the formula (1) that also contain in seperation film
Form what is realized using some interactions (effect for utilizing the mutual winding between molecule to realize etc.) between high polymer material
It is firm to combine, therefore the overlay film of the high polymer material containing formula (1) will not be peeled off, blood compatibility is very good.
Blood processor is preferred for haemodialyser, blood filter, blood filtration dialyzer etc., is more preferably used as making
For the continuous schedule haemodialyser of the purposes of their continuation, continuous schedule blood filter, continuous schedule blood filtration dialyzer.
The detail specifications such as size, the fractionation property of seperation film are determined according to each purposes.
Illustrated sequentially for the manufacture method of the blood processor of present embodiment.
The manufacture method of the blood treatment seperation film of present embodiment includes：Manufacture at least containing polysulfones system macromolecule and
The process of the seperation film of PVP；Contain formula with least a portion coating on the surface of aforementioned separation membrane
(1) process of the coating fluid of high polymer material, water and organic solvent.
And then it can also include the moisture containing ratio of seperation film being dried to process below 10 mass %, for blood
The process that processing carries out radiation sterilizing with seperation film in the case where oxygen concentration is more than 15% atmosphere.
Seperation film can be by using film stoste, the profit at least containing polysulfones system macromolecule and PVP
Prepared with usual way film.
, can be by the way that polysulfones macromolecule and PVP be dissolved in into solvent to manufacture as film stoste.
As above-mentioned solvent, such as dimethyl acetamide, dimethyl sulfoxide (DMSO), METHYLPYRROLIDONE, two can be included
NMF, sulfolane, He dioxanes etc..
It as solvent, can be used alone, two or more mixed solvents can also be used.
For film stoste in the high molecular concentration of polysulfones system, if in can be film-made and resulting film have make
To be then not particularly limited in the range of concentration as the performance through film, it is preferred that being 5~35 mass %, more preferably 10
~30 mass %.In the case of reaching high water permeability, polysulfones system resin concentration is low to be advisable, more preferably 10~25 matter
Measure %.
Do not limit, such as be preferably for the PVP concentration in film stoste, be adjusted with
Make PVP relative to the high molecular ratio of polysulfones system (quality/polystyrene of PVP
High molecular quality) be preferably below 27 mass %, more preferably 18~27 mass %, further preferred 20~27 mass %.
It is set to below 27 mass %, can be suppressed relative to the high molecular ratio of polysulfones system by PVP
The stripping quantity of PVP.It is further preferred, that by being set to more than 18 mass %, can be by separation membrane surface
PVP concentration be controlled in suitable scope, improve suppress protein absorption effect, blood can be formed
Liquid blood treatment seperation film excellent in compatibility.
Film stoste that can be more than use, using commonly used approach, manufacture the separation of flat film, hollow-fibre membrane
Film.
Illustrated for one of the manufacture method of hollow-fibre membrane.
Using the spinning-nozzle of pore (tube in orifice) type, by the hole of the spinning-nozzle will be film-made spinning solution,
By pipe by for making the hollow interior liquid of film spinning solution solidification while being ejected into aerial.As hollow interior liquid, can use
Water, the liquid of main body is used as using water, it is usually preferred to use the solvent and the mixed solution of water used in film spinning solution.Such as
Dimethylacetamide amine aqueous solution using 20~70 mass % etc..
, can be by the internal diameter and film of hollow-fibre membrane by adjusting film spinning solution spray volume and hollow interior liquid spray volume
Thickness is adjusted to desired value.
It is not particularly limited for the internal diameter of hollow-fibre membrane, in blood treatment purposes being usually 170~250 μm is
Can, preferably 180~220 μm.Removed from the diffusion as the low molecule amount thing realized using material moving resistance through film
From the viewpoint of, preferably the thickness of hollow-fibre membrane is less than 50 μm.
In addition, from the viewpoint of intensity, more preferably more than 10 μm.
By the film spinning solution that spinning-nozzle sprays together with hollow interior liquid in the traveling of air gap portion, it is then introduced into and sets
Be placed in spinning-nozzle bottom using water as the coagulating bath of main body in, impregnate certain time, complete its solidification.Now, preferably with
It is less than 1 to be film-made spinning solution to spray the drawing-off that the ratio between linear velocity and hauling speed represent.
It should be noted that air gap refers to the space between spinning-nozzle and coagulating bath, film spinning solution by by
The poor solvent compositions such as the water in the hollow interior liquid that spinning-nozzle sprays simultaneously are (for polysulfones system macromolecule and polyvinylpyrrolidine
The poor solvent composition of alkanone), solidified by inner surface side.Smooth separation membrane surface is formed when solidifying and starting, in order to
Make seperation film Stability Analysis of Structures, drawing-off is preferably less than 1, more preferably less than 0.95.
Then, by using the washing of hot water etc., after removal residues in the solvent of hollow-fibre membrane, continuously it imported into dry
In dry machine, the hollow-fibre membrane that can have been dried by hot blast etc..In order to remove unwanted PVP,
Preferably by more than 60 DEG C of hot water implement washing in more than 120 seconds, more preferably using more than 70 DEG C of hot wash 150 seconds with
On.
Due to being embedded in rear process with polyurethane resin, in addition, in the present embodiment, in order to be carried out with drying regime
Radiation sterilizes, and the moisture containing ratio that seperation film is preferably made by drying is below 10 mass %.
The hollow-fibre membrane that process by the above obtains can be have adjusted length and radical to form desired film
The form of the beam of area is for component manufacturing process.In the process, hollow-fibre membrane is filled near the both ends of side
Cylindrical container with 2 nozzles, both ends are embedded with polyurethane resin.
Then the carbamate moiety that have cured at both ends is cut off and is processed as hollow-fibre membrane opening (exposing)
End.The head-shield of the nozzle of (export) is imported with liquid to both ends filling, forms the shape of blood processor.
After assembling assembly as described above, the coating fluid of the high polymer material containing formula (1) is injected into hollow-fibre membrane
It is interior, thus it can also form the overlay film containing PVP in separation membrane surface.
Carried out in detail sequentially for the method for the overlay film that the high polymer material containing formula (1) is formed on the surface of seperation film
Explanation.
In present embodiment, such as can be by high polymer material of the surface of the seperation film coating comprising formula (1)
Coating fluid forms overlay film.
Coating fluid is if insoluble polysulfones system macromolecule, the solvent for the high polymer material that can be dissolved or disperse formula (1)
It is not particularly limited.The high polymer material of formula (1) passes through between the PVP that contains in seperation film
Interaction etc., has strong compatibility, therefore the species regardless of coating fluid for seperation film, can easily divide
It is excellent from forming the overlay film on film, but from the viewpoint of the operation in the security, ensuing drying process from process is good
Elect water, alcohol solution as.From the viewpoint of boiling point, toxicity, suitably using water, ethanol water, methanol aqueous solution and different
Aqueous propanol solution etc..
But in order to increase the amount of the high polymer material of the formula in top layer (1), for the kind of the solvent of coating fluid
Class, the composition of solvent using with being also included within as the relation of the seperation film for being applied base material, it is necessary to interior consider as mentioned before.
Do not limited for the concentration of the high polymer material of the formula (1) of coating fluid, such as can be the 0.001 of coating fluid
The mass % of the mass %, more preferably 0.005 mass % of quality %~1~0.3.
Do not limited for the coating method of coating fluid, such as can use and seperation film is injected into by the head-shield with nozzle
Method that is upper, then being removed unnecessary solution using compressed air.
Preferably it is dried after coating, is not limited for drying means, can be dried under reduced pressure or heat drying is to constant.
The temperature that the temperature of heat drying will not be deteriorated if the component of component is then just because the time for taking into account process, appropriate setting are
Can.
Separated for the blood treatment that there is the high polymer material of formula (1) in separation membrane surface obtained as described above
Film, it is possible to implement radiation sterilization treatment.For carry out radiation sterilization treatment atmosphere do not limit, oxygen concentration 15% with
On atmosphere so that even if under air, the ground such as the denaturation of seperation film can not also be caused to implement radiation sterilizing.
Radiation sterilization can use electron beam, gamma-rays, X ray etc., can use any one.For radiation
Exposure dose, electron beam, it is gamma-ray in the case of, generally with 15~50Kgy, preferably with 15~40Kgy or 20~40Kgy
Dosage range be irradiated.By sterilization process such as this radiation sterilizings, blood processor is completed.
Embodiment
Embodiment described below and comparative example, are specifically described for the present invention, but the present invention is not implemented by these
Example is limited.
(1) infrared ATR (total reflection method) measure
The step of sample, is as described below.
By the inner surface distilled water of hollow fibre shape seperation film with every 1.5m2100ml/ minutes wash within 5 minutes
Wash, thus carry out startup filling (priming).The blood processor after filling will be started to decompose, split what is sampled with razor
Doughnut, make hollow fiber separating film surface upward, press prism for any 10 positions of the part, carry out infrared
ATR is determined.(650cm-1~4000cm-1) prism use Japan Spectroscopy Corporation ATR-30-Z (ZnSe, refractive index
2.4), incidence angle is set to 60 degree.
The 1735cm of high polymer material from formula (1)-1The peak intensity of neighbouring ester group-O-C=O infrared absorption peak
Area (1715cm-1And 1755cm-1Peak area as baseline) it is set to P1, the 1595cm from polysulfones-1Neighbouring C=C's is red
Peak intensity area (the 1555cm of outer absworption peak-1And 1620cm-1Peak area as baseline) P2 is set to, by the flat of the ratio between P1/P2
The amount of the high polymer material of the formula (1) of average measure separation membrane surface.
(2) thermal cracking gas chromatography mass spectral analysis
Using following device, thermal cracking gas chromatography mass spectral analysis is carried out under the following conditions.
Device name Agilent 5973N-MSD (Agilent systems)
Thermal cracker name Double-Shot Pyrolyzer Py-2020iD (Frontier Laboratories
Ltd. make)
Chromatographic column name HP-5MS
Chromatographic column summary length 30m, internal diameter 0.25mm, 0.25 μm of thickness, phenyl methyl siloxane film
0 second thermal cracking temperature/time 600 DEG C
320 DEG C of thermal cracker interface (interface) temperature
320 DEG C of GC injection temperatures
GC baking ovens temperature at initial stage/40 DEG C of retention time/3 minutes
10 DEG C/min of GC baking ovens programming rate
GC baking ovens reach temperature/retention time 300 DEG C/0 minute
300 DEG C of MS delivery pipes temperature
230 DEG C of MS ionization sources temperature
150 DEG C of MS quadrupoles temperature
MS ionizing voltages/electric current 70eV/35 μ A
MS scanning ranges 29-550
(3) UFR (ml/HrmmHg) measure
Circulated stoste with 100ml/ minutes towards blood side outlet (bout) by the blood side entrance (bin) of blood processor
(Urea=1000ppm, VB-12 (vitamin B12)=10ppm/ pure water), by dialysis fluid side entrance (din) towards dialysis fluid side
Circulated pure water with 500ml/ minutes in the direction intersected with stoste outlet (dout).
UFR is represented with following formula.
UFR (ml/HrmmHg)={ bin flow (ml/ minutes) × 60 (minute/hour (Hr)) × UFR coefficients }/
TMP={ 100 × 60 × UFR coefficients }/TMP
Here, UFR coefficients are reference pressure when calculating UFR measured values.In addition, TMP (mmHg) goes out to clog blood side
The pressure applied during mouth (bout) portion for blood treatment with seperation film, is represented with following formula.
TMP={ (Pbin+Pbout)-(Pdin+Pdout) }/2
(4) measure of contact angle
By the inner surface distilled water of hollow fibre shape seperation film with every 1.5m2100ml/ minutes wash within 5 minutes
Wash, thus carry out startup filling.The blood processor after filling will be started to decompose, sampled doughnut is splitted with razor,
Make hollow fiber separating film surface on to determine contact angle.
Then, repeat with every 1.5m2The startup that 100ml/ minutes wash 5 minutes fills 5 times, confirms doughnut separation
The presence or absence of the change of contact angle on film surface.
(5) measure of blood compatibility lactic dehydrogenase (LDH) activity and residual red root number
The blood compatibility of seperation film is evaluated the tack on film surface with blood platelet, will attach to the blood platelet of film
In the activity of lactic dehydrogenase (LDH) that contains carry out quantification as index.
By using physiological saline (great mound normal saline solution, Otsuka Pharmaceutical Co., Ltd) washed blood processor, enters
Row starts filling.The blood processor after filling will be started to decompose, seperation film is gathered, effective length is formed with the seperation film gathered
Spend 15cm, the area of film inner surface is 5 × 10-3m2Mode by both ends with epoxy (Bond Quickset, Konishi Co.,
Ltd.) it is processed, makes micromodule.For the micromodule, physiological saline 10ml is set to enter in doughnut circulating inside
Row washing.
Then, addition is made to have the people blood 15ml (heparin 1000IU/L) of heparin with the flow velocity of 1.3ml/ minutes in above-mentioned making
Micromodule in circulated 4 hours at 37 DEG C.Using physiological saline, inner side 10ml for micromodule, for outside
Washed respectively with 10ml.By the length 7cm of the whole half of the micromodule collection washed hollow-fibre membrane
Afterwards, blocked, the centrifuge tube (Spitz tube) of LDH measure is added to, as measurement sample.In addition, naked eyes judge
Doughnut in micromodule produces several residual blood (blood solidifies in doughnut).
Then, TritonX-100 will be dissolved in phosphate buffer solution (PBS) (Wako Pure Chemical Industries, Ltd.)
0.5 volume % TritonX-100/PBS solution 0.5ml obtained from (Nacalai Tesque companies) is added to LDH measure
After centrifuge tube, 60 minutes oscillation treatments are carried out, the cell (mainly blood platelet) that will attach to seperation film destroys, and extracting is thin
LDH in born of the same parents.The extract point is taken into 0.05ml, and then add 0.6mM sodium pyruvate solution 2.7ml, 1.277mg/ml
NADH (NADH) solution 0.3ml, its 340nm absorbance is determined after being reacted 1 hour at 37 DEG C.
Similarly determine absorbance for the seperation film (blank) not with reaction of blood, using following formula calculate absorbance it
Poor △ Abs (340nm)/Hr.
△ Abs (340nm)/Hr=[Abs (340nm) after the 1Hr of blank (the non-contact film of blood)]-[(blood connects sample
Touch film) 1Hr after Abs (340nm)]
Then, for single seperation film (this time comparative example containing polysulfones system macromolecule and PVP
1) value similarly is calculated as ratio value when 100 as control sample measure △ Abs (340nm)/Hr.
In this method, the LDH activity using the ratio value as each sample.Mean blood platelet to film if LDH activity height
The adhesion amount on surface is more, blood compatibility is low.It should be noted that measure is carried out 3 times, recorded with its average value.
The seperation film excellent as blood compatibility, preferably seperation film of the LDH activity less than 25, more preferably LDH activity are 5
Following seperation film, the seperation film that LDH activity is less than 2 may determine that blood compatibility is very excellent.
(6) evaluation test of inflammatory model blood has been used
The patient of the treatment of haemodialyser, blood filter, blood filtration dialyzer etc. is needed to use, although journey be present
The difference of degree is still in inflammatory conditions mostly.The blood of the known patient in inflammatory conditions is activated, inflammatory mark
Generation is hyperfunction, coagulation system is hyperfunction, compared with the blood of Healthy People, character significantly deviates from, it is known that is handled with seperation film
In the case of, the useful proteins matter such as albumin, fibrinogen in blood is easily adsorbed at seperation film.
When therefore carrying out blood compatibility evaluation, in addition to having used the evaluation of blood of Healthy People, use
The evaluation of following inflammatory model blood is also useful.
The method for making of (6-1) inflammatory model blood
The use of inflammatory model blood is by pacifying field (N.Yasuda, et al., J.Surg.Research, 176,2012) etc.
Method disclosed in people is implemented.
That is, after heparin 1000IU/L is taken a blood sample as anticoagulant by Healthy People, with blood level 1.0 × 10-4mg/
Ml addition lipopolysaccharides (LPS：Lipopolysaccharide after) (being derived from O-127 Sigma-Aldrich Co.LLC), at 39 DEG C
Lower culture 1.5 hours, is thus made inflammatory model blood.
(6-2) has used blood compatibility evaluation and the index of inflammatory model blood
Inflammatory model blood 20mL is as blood pool (pool) made of will be above-mentioned, to the face that have adjusted film forming inner surface
Product is 5 × 10-3m2Hollow fiber type blood processor, with the flow rate 30 of 1.0ml/ minutes/after, with 10ml life
Reason salt solution carries out returning blood.After returning blood, hollow fiber membrane-type blood processor is disassembled, takes out seperation film, will be equivalent to 15cm2's
The seperation film of membrane area is blocked, and putting into addition has 1%SDS (lauryl sulfate sodium water solution) solution 2ml micro-pipe, with
1850rpm vibrations extracting 1 hour, as seperation film attachment protein quality determination sample.
For the protein concentration in extract, BCA Protein Assay Kit (Thermo Fisher are used
Scientific Inc. (Waltham, MA, USA) make) it is measured, calculate the gross protein adhesion amount of every 1ml extracts.
(7) there is the making of the high polymer material of structure shown in formula (1)
(A) PEt2A (poly- [acrylic acid 2- (2- ethoxy ethoxies) ethyl ester]) making
For acrylic acid 2- (2- ethoxy ethoxies) ethyl ester 15g, in the dioxane 60g of Isosorbide-5-Nitrae-, by azobis isobutyronitrile
(0.1 weight %) is used as initiator, while blasting nitrogen, carries out polymerizeing for 10 hours at 75 DEG C., will after polymerisation terminates
Resulting polymeric solution is added drop-wise to n-hexane, makes product precipitation, separation.Resulting product is dissolved in tetrahydrofuran, entered
And n-hexane is used to carry out 2 purifying.Purified is dried under reduced pressure diel.Obtain the polymer of water white transparency and malt sugar shape.
Receipts amount (yield) is 12.0g (80.0%).
Resulting polymer architecture passes through1H-NMR confirms.
In addition, the result analyzed from GPC molecular weight, its number-average molecular weight (Mn) is 11600, molecular weight distribution
(Mw/Mn) it is 3.9.
(B) PMe2MA (poly- [methacrylic acid 2- (2- methoxy ethoxies) ethyl ester]) making
It is in the dioxane 50g of Isosorbide-5-Nitrae-, azo is double different for methacrylic acid 2- (2- methoxy ethoxies) ethyl ester 10g
Butyronitrile (0.1 weight %) is used as initiator, while blasting nitrogen, carries out polymerizeing for 8 hours at 80 DEG C.Polymerisation terminates
Afterwards, resulting polymeric solution is added drop-wise to n-hexane, makes product precipitation, separation.Resulting product is dissolved in tetrahydrochysene furan
Mutter, and then 2 purifying are carried out using n-hexane.Purified is dried under reduced pressure diel.Obtain the poly- of water white transparency and malt sugar shape
Compound.Receipts amount (yield) is 8.2g (82.0%).
Resulting polymer architecture passes through1H-NMR confirms.
In addition, the result analyzed from GPC molecular weight, its number-average molecular weight (Mn) is 104300, molecular weight distribution
(Mw/Mn) it is 4.6.
(C) PEt2MA (poly- [methacrylic acid 2- (2- ethoxy ethoxies) ethyl ester]) making
It is in the dioxane 60g of Isosorbide-5-Nitrae-, azo is double different for methacrylic acid 2- (2- ethoxy ethoxies) ethyl ester 15g
Butyronitrile (0.1 weight %) is used as initiator, while blasting nitrogen, carries out polymerizeing for 2 hours at 75 DEG C.Polymerisation terminates
Afterwards, resulting polymeric solution is added drop-wise to n-hexane, makes product precipitation, separation.Resulting product is dissolved in tetrahydrochysene furan
Mutter, and then 2 purifying are carried out using n-hexane.Purified is dried under reduced pressure diel.Obtain the poly- of water white transparency and malt sugar shape
Compound.Receipts amount (yield) is 5.2g (34.7%).
Resulting polymer architecture passes through1H-NMR confirms.
In addition, the result analyzed from GPC molecular weight, its number-average molecular weight (Mn) is 142500, molecular weight distribution
(Mw/Mn) it is 6.1.
(D) PMC3A (poly- [acrylic acid 3- methoxyl groups propyl ester]) making
(D-1) synthesis of acrylic acid 3- methoxyl groups propyl ester (with reference to following formula)
Under stream of nitrogen gas, triethylamine 15.5g (153 mMs), 3- first are added to 3 neck eggplant type flasks (capacity 500mL)
Oxy-1-propyl alcohol 13.5g (150 mMs) and Anaesthetie Ether 200mL, reaction system is cooled to 0 DEG C with ice-water bath.Carry out
After acryloyl chloride 14.0g (155 mMs) was added dropwise with 30 minutes to reaction system while stirring, it is small to be stirred at room temperature 12
When.The end of reaction passes through1After H NMR confirm, stop reaction.By the white precipitation for carrying out and generating with reaction by taking out
Filter to remove, reaction dissolvent is distilled by rotary evaporator by resulting filtrate and removed, obtain reaction production in liquid form
Thing.Resulting reaction product passes through silica gel column chromatography (developing solvent hexane:Anaesthetie Ether=100:0~90:10) separate pure
After change, and then purified by being evaporated under reduced pressure in the presence of calcium hydride, obtain transparency liquid 9.95g (69.1 millis
Mole, yield 46% (MC3A conversions)).
Its boiling point is 24.5 DEG C~25.5 DEG C/0.08mmHg,1H-NMR(500MHz、CDCl3) parsing result, be accredited as
Acrylic acid 3- methoxyl group propyl ester.
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=6.39 (d, J=17.3Hz, 1H),
6.11 (dd, J=17.3Hz, 10.4Hz, 1H), 5.81 (d, J=10.4Hz, 1H), 4.24 (t, J=6.4Hz, 2H), 3.45 (t,
J=6.3Hz, 2H), 3.33 (s, 3H), 1.93 (p, J=6.4Hz, 2H)13C-NMR(125MHz、CDCl3)：δ=166.2,
130.6,128.5,69.1,61.7,58.7,29.0
(D-2) manufacture of poly- [acrylic acid 3- methoxyl groups propyl ester] (with reference to following formula)
The acrylic acid 3- methoxyl group propyl ester 7.50g (52.0 obtained to the addition of 3 neck eggplant type flasks (capacity 100mL) in above-mentioned
MM), 1,4- dioxanes 30.2g and azobis isobutyronitrile 7.5mg (0.047 mM).Drying nitrogen is circulated in into reaction
Stirred 30 minutes while in solution, reaction system is subjected to nitrogen displacement.The bottom of 3 neck eggplant type flasks is impregnated in into temperature to set
Due to 75 DEG C of oil bath, stir 6 hours under stream of nitrogen gas, thus polymerize.Polymerisation pass through1H NMR are true
Recognize, it is thus identified that after fully high reaction conversion ratio (90% or so), paradigmatic system is naturally cooled into room temperature, thus stopped anti-
Should.By the way that polymeric solution is added drop-wise into hexane, polymer is precipitated, remove supernatant by being decanted, sediment is dissolved in four
Hydrogen furans is reclaimed.Repetition be dissolved in tetrahydrofuran after, with the operation 2 times of hexane reprecipitation, purified, will be resulting
Sediment further stirs 24 hours in water.Go to remove water by decantation, sediment is dissolved in into tetrahydrofuran is reclaimed.Will
After solvent under reduced pressure distillation removes, it is dried with vacuum drier, obtains polymer 6.47g (yield 86% (PMC3A conversions)).
Using a part for resulting polymer, molecular weight is determined, as a result number-average molecular weight (Mn) is 31000 and divided
Son amount distribution (Mw/Mn) is 2.5.It is as a result -48.0 DEG C in addition, determining the glass transition temperature of the polymer,1H-NMR
(500MHz、CDCl3) parsing result, be accredited as poly- [acrylic acid 3- methoxyl groups propyl ester].
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=4.10 (br, 2H), 3.41 (brt,
2H)、3.31(s,3H)、2.26(s,1H)、1.86-1.62(m,4H).13C-NMR(125MHz、CDCl3)：δ=174.3,69.1,
62.0,58.6,41.5,29.0,0.07.
(E) PMC4A (poly- [acrylic acid 4- methoxybutyls]) making
(E-1) synthesis of acrylic acid 4- methoxybutyls (with reference to following formula)
(E-1-1) synthesis of 4- methoxyl groups-n-butyl alcohol
Under stream of nitrogen gas, BDO 53.6g (600 mMs) and four are added to 3 neck eggplant type flasks (capacity 500mL)
Hydrogen furans 300mL, suitably cool down while stirring, and a small amount of every time add sodium hydride 18.1g (450 mMs).Sodium hydride
After the addition of total amount terminates, stir 1 hour at room temperature, iodomethane 63.4g (450 mMs) is added dropwise, and then stir 14 hours.
Pass through1After H NMR confirm that reaction is carried out, add a small amount of water and stop reaction.After solution is formed acidity by 2N hydrochloric acid, pass through
Rotary evaporator, which distills tetrahydrofuran, to be removed.After into resulting reactant mixture, addition Anaesthetie Ether is diluted, add
Enter anhydrous magnesium sulfate to be dried.Magnesium sulfate and sediment are removed by filtering by the diethyl ether solution dried, it is resulting
Filtrate concentrated by rotary evaporator.Resulting concentrate (as developing solvent, uses oneself successively by the use of silica gel column chromatography
Alkane, dichloromethane, methanol) isolated and purified after, concentrated, obtain transparency liquid 18.5g (178 mMs, yield
29.6%).Its boiling point is 50.0 DEG C/0.08mmHg,1H-NMR(500MHz、CDCl3) parsing result, be accredited as poly- 4- methoxies
Base-n-butyl alcohol.
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=3.58 (t, J=6.0Hz, 2H),
3.38 (t, J=6.0Hz, 2H), 3.31 (s, 3H), 2.20 (s, 1H), 1.61 (m, 4H)13C-NMR(125MHz、CDCl3)：δ=
72.8,62.6,58.6,30.1,26.7.
(E-1-2) synthesis of acrylic acid 4- methoxybutyls
4- methoxyl groups-n-butyl alcohol 15.8g (150 mMs) of synthesis in (E-1-1) is used, is set to triethylamine 17.5g
(165 moles), Anaesthetie Ether 250mL, acryloyl chloride 14.5g (158 mMs), are in addition obtained in the same manner as (D-1)
Prescribed liquid 11.4g (72.2 mMs, yield 48%).
Its boiling point is 50 DEG C/0.08mmHg,1H-NMR(500MHz、CDCl3) parsing result, be accredited as acrylic acid 4- first
Epoxide butyl ester.
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=6.47 (d, J=15Hz, 1H),
6.20 (dd, J=8.75Hz, 5.0Hz, 1H), 5.89 (d, J=10.5Hz, 1H), 4.26 (t, J=6.5Hz, 2H), 3.49 (t, J
=6.5Hz, 2H), 3.42 (s, 3H), 1.84~1.75 (m, 4H)13C-NMR(125MHz、CDCl3)：δ=166.3,130.5,
128.6,72.2,64.6,58.6,26.2,25.5.
(E-2) manufacture of poly- [acrylic acid 4- methoxybutyls] (with reference to following formula)
Using obtain in above-mentioned acrylic acid 4- methoxybutyls 9.41g (59.5 mMs), 1,4- dioxanes 41.2g,
Azobis isobutyronitrile 10mg (0.061 mM), polymerization time are set to 8 hours, in addition polymerize in the same manner as (D-2)
Thing 7.21g (yield 77% (PMC4A conversions)).
Using a part for resulting polymer, molecular weight is determined using following methods, as a result number-average molecular weight
(Mn) be 29000 and molecular weight distribution (Mw/Mn) is 2.2.In addition, the glass transition temperature of the polymer is determined, as a result
For -64.6 DEG C,1H-NMR(500MHz、CDCl3) parsing result, be accredited as poly- [acrylic acid 4- methoxybutyls].
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=4.03 (br, 2H), 3.37 (t, J
=6.0Hz, 2H), 3.30 (s, 3H), 2.24 (s, 1H), 1.87-1.59 (m, 6H)13C-NMR(125MHz、CDCl3)：δ=
174.3,72.1,64.4,58.5,41.4,35.0,26.1,25.4.
(F) PMC5A (poly- [acrylic acid 5- methoxyl groups pentyl ester]) making
(F-1) synthesis of acrylic acid 5- methoxyl groups pentyl ester (with reference to following formula)
(F-1-1) synthesis of 5- methoxyl groups -1- amylalcohols
Using 1,5-PD 31.4g (300 mMs), tetrahydrofuran 200mL, sodium hydride 12.3g (300 mmoles are set to
You), iodomethane 43.8g (300 mMs), transparency liquid 14.4g (122 mmoles are in addition obtained in the same manner as (E-1-1)
You, yield 41%).Its boiling point is 60 DEG C~64 DEG C/0.08mmHg,1H-NMR(500MHz、CDCl3) parsing result, be accredited as
5- methoxyl group -1- amylalcohols.
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=3.61 (m, 2H), 3.36 (t, J=
7.5Hz, 2H), 3.31 (s, 3H), 1.85~1.35 (m, 7H)13C-NMR(125MHz、CDCl3)：δ=72.8,62.6,58.6,
32.5,29.3,22.4.
(F-1-2) synthesis of acrylic acid 5- methoxyl groups pentyl ester
5- methoxyl group -1- amylalcohols the 15.4g (130 mMs) of synthesis in (F-1-1) are used, are set to triethylamine 14.5g
(143 moles), Anaesthetie Ether 200mL, acryloyl chloride 12.4g (136.5 mMs), are in addition obtained in the same manner as (D-1)
Transparency liquid 5.95g (34.6 mMs, yield 27%).Its boiling point is 58 DEG C~71 DEG C/0.08mmHg,1H-NMR(500MHz、
CDCl3) parsing result, be accredited as 5- methoxyl group -1- amylalcohols.
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=6.36 (d, J=18.0Hz, 1H),
6.11 (dd, J=5.0Hz, 8.8Hz, 1H), 5.79 (d, J=9.5Hz, 1H), 4.17 (t, J=7.0Hz, 2H), 3.38 (t, J=
6.3Hz, 2H), 3.31 (s, 3H), 1.67~1.58 (m, 4H), 1.43 (m, 2H)13C-NMR(125MHz、CDCl3)：δ=
166.4,130.6,128.6,72.6,64.6,58.6,29.3,28.5,22.7.
(F-2) manufacture of poly- [acrylic acid 5- methoxyl groups pentyl ester] (with reference to following formula)
Use the acrylic acid 5- methoxyl group pentyl esters 5.01g (32.1 mMs), 1,4- dioxanes 20g, idol obtained in above-mentioned
The double isobutyronitrile 5mg (0.030 mM) of nitrogen, polymerization time are set to 8 hours, in addition obtain polymer in the same manner as (D-2)
3.64g (yield 73%).
Using a part for resulting polymer, molecular weight is determined using following methods, as a result number-average molecular weight
(Mn) be 50000 and molecular weight distribution (Mw/Mn) is 2.3.In addition, the glass transition temperature of the polymer is determined, as a result
For -77.6 DEG C,1H-NMR(500MHz、CDCl3) parsing result, be accredited as poly- [5- methoxyl group -1- amylalcohols].
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=4.00 (br, 2H), 3.36 (t, J
=6.5Hz, 2H), 3.31 (s, 3H), 2.24 (m, 1H), 1.87-1.38 (m, 8H)13C-NMR(125MHz、CDCl3)：δ=
174.3,72.5,64.6,58.6,41.5,29.3,28.5,23.5.
(G) PMC6A (poly- [the own ester of acrylic acid 6- methoxyl groups]) making
(G-1) synthesis of the own ester of acrylic acid 6- methoxyl groups (with reference to following formula)
(G-1-1) synthesis of 6- methoxyl groups -1- hexanols
Using 1,6- hexylene glycols 35.6g (300 mMs), tetrahydrofuran 230mL, sodium hydride 12.4g (300 mmoles are set to
You), iodomethane 42.6g (300 mMs), transparency liquid 10.2g (77.2 mmoles are in addition obtained in the same manner as (E-1-1)
You, yield 26%).Its boiling point is 94.0 DEG C~100 DEG C/0.08mmHg,1H-NMR(500MHz、CDCl3) parsing result, mirror
It is set to 6- methoxyl group -1- hexanols.
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=3.62 (t, J=6.5Hz, 2H),
3.35 (t, J=6.8Hz, 2H), 3.31 (s, 3H), 1.65~1.36 (m, 9H)13C-NMR(125MHz、CDCl3)：δ=72.8,
62.8,58.5,32.7,29.6,25.9,25.6.
(G-1-2) synthesis of the own ester of acrylic acid 6- methoxyl groups
6- methoxyl group -1- hexanols the 9.25g (70.0 mMs) of synthesis in (G-1-1) are used, are set to triethylamine 6.65g
(73.5 moles), Anaesthetie Ether 200mL, acryloyl chloride 6.65g (73.5 mMs), are in addition obtained in the same manner as (D-1)
Transparency liquid 5.77g (31.0 mMs, yield 44%).Its boiling point is 99 DEG C~103 DEG C/0.08mmHg,1H-NMR
(500MHz、CDCl3) parsing result, be accredited as the own ester of acrylic acid 6- methoxyl groups.
It is described below1The result of H-NMR parsings.1H-NMR(500MHz、CDCl3)：δ=6.36 (d, J=18.0Hz, 1H),
6.09 (dd, J=5.3Hz, 8.8Hz, 1H), 5.79 (d, J=12.0Hz, 1H), 4.13 (t, J=7.0Hz, 2H), 3.35 (t, J
=6.8Hz, 2H), 3.31 (s, 3H), 1.66~1.56 (m, 4H), 1.37 (m, 4H)13C-NMR(125MHz、CDCl3)：δ=
166.4,130.5,128.6,72.7,64.6,58.6,29.6,26.8,25.8.
(G-2) manufacture of poly- [the own ester of acrylic acid 6- methoxyl groups] (with reference to following formula)
Using obtain in above-mentioned the own ester 5.05g of acrylic acid 6- methoxyl groups (28.0 mMs), 1,4- dioxanes 25.1g,
Azobis isobutyronitrile 5.03mg (0.030 mM), polymerization time are set to 8 hours, in addition gathered in the same manner as (D-2)
Compound 3.75g (yield 74%).
Using a part for resulting polymer, molecular weight is determined using following methods, as a result number-average molecular weight
(Mn) be 29000 and molecular weight distribution (Mw/Mn) is 2.5.In addition, the glass transition of the polymer is determined with following methods
Temperature, as a result as shown in the table is -77.4 DEG C,1H-NMR(500MHz、CDCl3) parsing result, be accredited as poly- [acrylic acid 6-
The own ester of methoxyl group].1H-NMR(500MHz、CDCl3)：δ=3.99 (br, 2H), 3.35 (t, J=6.5Hz, 2H), 3.31 (s,
3H)、2.24(m,1H)、1.58-1.35(m,10H).13C-NMR(125MHz、CDCl3)：δ=174.7,72.7,64.6,58.6,
41.5,35.4,29.6,28.6,25.9,25.8.
(8) deliquescent confirmation of the high polymer material of formula (1) for various solvents
In order to make coating fluid, confirm in (7) manufactured PEt2A, PMe2MA, PEt2MA, PMC3A, PMC4A, PMC5A and
Dissolubilities of the PMC6A for various solvents.
As a result as shown in following table.
Understand in ethanol/water system, according to the mix ratio of second alcohol and water, the dissolubility of the high polymer material of formula (1) is not
Together.
[table 1]
Ethanol/water system (25 DEG C)
[table 2]
Ethanol/water system (25 DEG C)
Dissolving：○
It is insoluble：×
(embodiment 1)
For being film-made spinning solution, at dimethyl acetamide (KISHIDA CHEMICAL Co., Ltd.s system, reagent are superfine)
Dissolved in 79 mass parts polysulfones (Solvay S.A. systems, P-1700) 17 mass parts and PVP (BASF SE systems,
K-90) 4 mass parts make.
Hollow interior liquid uses the mass % aqueous solution of dimethyl acetamide 60.
Film spinning solution and hollow interior liquid are sprayed by the spinning-nozzle of pore type.The temperature of film spinning solution during ejection
Spend for 40 DEG C.The film spinning solution sprayed is passed through to 60 DEG C of the solidification for being impregnated in the portion of falling of cover covering and being formed by water
Bath is solidified.Spinning speed is 30m/ minutes.
After solidification, washed, dried, obtain hollow shape seperation film.Washing temperature is set to 90 DEG C, washing time is set to
180 seconds.It should be noted that adjusted in a manner of dried thickness is 35 μm, internal diameter is 185 μm film spinning solution and in
The spray volume of liquid in sky.
Resulting hollow fiber separating film group is entered to blood processor to be molded, composition effective area 1.5m2's
Component.Then PEt2A (Mn 11600, Mw/Mn 3.9) 0.1g is dissolved in the ethanol 35g/ water 65g aqueous solution (100g),
Make coating fluid.Vertical to hold assembled component, portion is circulated coating fluid with flow velocity 100ml/ minutes from it, makes seperation film table
Face contacts with coating fluid.
The blood processor obtained for the time point, implement Hemocompatibility Tests, as a result LDH activity is 0.2.
After coating fluid contact, the coating fluid in component is blown away with 0.1KMpa air, group is put into vacuum drier
Part, it is dried in vacuo 15 hours at 35 DEG C, implements γ ray sterilization under air atmosphere, under 25Kgy, obtain blood processor.
Implement Hemocompatibility Tests for resulting blood processor, as a result LDH activity be 0.2, residual red root number be
0.Understand under air, radiation sterilizing is carried out under drying regime, blood compatibility also hardly reduces.
Infrared ATR measure is carried out for the sample.Its infrared absorption curve is as shown in Figure 1.
Confirm the infrared absorption (1735cm from PEt2A-1Near) ester group (- O-C=O) peak.
In addition, infrared absorption (1735cm-1Near) peak intensity area P1 and infrared absorption (1595cm-1Near) peak intensity
The ratio between area P2 P1/P2 is 0.089.
Thermal cracking gas chromatography mass spectral analysis is carried out for the sample.
Its result is as shown in Figure 3.In addition, as control, carry out thermal cracking gas chromatography mass spectral analysis for PEt2A and obtain
Result it is as shown in Figure 2.
The peak of the chromatogram of PEt2A hot lysate is in RT7.9 minutes nearby (Fig. 2), and same vestige is in the examination
Sample is also found (Fig. 3).Then from mass spectrographic retrieval result (Fig. 4), the peak is 2- (2- ethoxy ethoxies) ethanol
Peak.Think that (pendant moiety) hot lysate hydrolysis that 2- (2- ethoxy ethoxies) ethanol is PEt2A forms, therefore can be with
Confirm, PEt2A be present in the separation membrane surface of embodiment 1.
It should be noted that (comparative example 1) is recorded hereinafter, for no coating PEt2A seperation film similarly
Thermal cracking gas chromatography mass spectral analysis is carried out, the vestige at peak is not as a result found in RT7.9 minutes.
Implement the measure of contact angle for the sample.
Its result is as shown in following table.
Contact angle is 60 ° or so, even if repeated priming fills, contact angle is also without discovery change.
[table 3]
| Start filling number | 1 | 2 | 3 | 4 | 5 |
| Contact angle ° | 58 | 57 | 56 | 57 | 57 |
For the sample, UFR (ml/HrmmHg) is determined, as a result UFR=470 (ml/HrmmHg).
(embodiment 2~6)
Hollow fiber separating film is manufactured similarly to Example 1, its group is entered to blood processor to be molded, composition has
Imitate area 1.5m2Component.
Then, the such as following table that mixes of the PEt2A concentration of coating fluid and water and organic solvent (ethanol) changes like that,
In addition blood processor, measure LDH activity, residual red root number, infrared absorption peak ratio are made similarly to Example 1.
As a result as shown in following table 4.
LDH activity somewhat improves if PEt2A concentration is increased, but without the big difference of discovery.
On the other hand, if mixed solvent ratio (ETOH/H2O) amount that change then has organic solvent increases, therewith, peak ratio
(P1/P2) reduce, i.e. the tendency of the PEt2A of separation membrane surface amount reduction, be additionally present of LDH activity increase, i.e. blood
The tendency that compatibility reduces.But in the range of LDH activity is all in value possessed by usual commercially available product.
[table 4]
Similarly to Example 1 for the sample of embodiment 2~6, solved using thermal cracking gas chromatography mass spectral analysis
Analysis.For whole samples, peak of the confirmation as the RT7.9 minutes at the peak of PEt2A hot lysate can by mass spectrographic retrieval result
Know, the peak is 2- (2- ethoxy ethoxies) ethanol.It is possible thereby to confirm in embodiment 2~6, also PEt2A be present on film surface.
(embodiment 7,8)
On being film-made spinning solution, relative to dimethyl acetamide (KISHIDA CHEMICAL Co., Ltd.s system, reagent
It is superfine) amount and PVP (BASF SE systems, K- of the polysulfones (Solvay S.A. systems, P-1700) of 79 mass parts
90) amount changes as shown in following table, in addition manufactures hollow fiber separating film similarly to Example 1, and group enters to blood
Liquid processor, PEt2A is coated with, determines LDH activity.
As a result as shown in following table.Formed even if change film stoste, LDH activity is also small, blood compatibility is good.
[table 5]
(embodiment 9)
Hollow fiber separating film is manufactured similarly to Example 1, its group is entered to blood processor to be molded, composition has
Imitate area 1.5m2Component.
PMe2MA (Mn 104300, Mw/Mn 4.6) 0.1g is then dissolved in the ethanol 20g/ water 80g aqueous solution
In (100g), coating fluid is made.Vertical to hold assembled component, portion is circulated coating fluid with flow velocity 100ml/ minutes from it,
Separation membrane surface is set to be contacted with coating fluid.
After coating fluid contact, the coating fluid in component is blown away with 0.1KMpa air, group is put into vacuum drier
Part, it is dried in vacuo 15 hours at 35 DEG C, implements γ ray sterilization under air atmosphere, under 25Kgy, obtain blood processor.
Implement Hemocompatibility Tests for resulting blood processor, as a result LDH activity be 1.7, residual red root number be
0。
Parsed from ATR, P1/P2 ratios are 0.039.
In addition, carry out thermal cracking gas chromatography mass spectral analysis for the sample.
The peak of the chromatogram of PMe2MA hot lysate was near RT12.7 minutes, and same vestige is in the sample
It is found.Then from mass spectrographic retrieval result (Fig. 5), the peak is methacrylic acid 2- (2- methoxy ethoxies) ethyl ester
Peak.Think that the hot lysate hydrolysis that methacrylic acid 2- (2- methoxy ethoxies) ethyl ester is PMe2MA forms, therefore can be with
Confirm, PMe2MA be present in the separation membrane surface of embodiment 9.
(embodiment 10)
Hollow fiber separating film is manufactured similarly to Example 1, its group is entered to blood processor to be molded, composition has
Imitate area 1.5m2Component.
PEt2MA (Mn 142500, Mw/Mn 6.1) 0.1g is then dissolved in the ethanol 40g/ water 60g aqueous solution
In (100g), coating fluid is made.Vertical to hold assembled component, portion is circulated coating fluid with flow velocity 100ml/ minutes from it,
Separation membrane surface is set to be contacted with coating fluid.
After coating fluid contact, the coating fluid in component is blown away with 0.1KMpa air, group is put into vacuum drier
Part, it is dried in vacuo 15 hours at 35 DEG C, implements γ ray sterilization under air atmosphere, under 25Kgy, obtain blood processor.
Implement Hemocompatibility Tests for resulting blood processor, as a result LDH activity be 2.3, residual red root number be
0。
Parsed from ATR, P1/P2 ratios are 0.039.
(embodiment 11)
For being film-made spinning solution, at dimethyl acetamide (KISHIDA CHEMICAL Co., Ltd.s system, reagent are superfine)
Dissolved in 79 mass parts polysulfones (Solvay S.A. systems, P-1700) 17 mass parts and PVP (BASF SE systems,
K-90) 4 mass parts make.
Hollow interior liquid uses the mass % aqueous solution of dimethyl acetamide 60.
By the spinning-nozzle of pore type, film spinning solution and hollow interior liquid are sprayed.Film spinning solution during ejection
Temperature is 40 DEG C.The film spinning solution sprayed is passed through coagulating for formed by water 60 DEG C is impregnated in the portion of falling of cover covering
Gu bath is solidified.Spinning speed is 30m/ minutes.
After solidification, washed, dried, obtain hollow shape seperation film.Washing temperature is set to 90 DEG C, washing time is set to
180 seconds.It should be noted that adjusted in a manner of dried thickness is 35 μm, internal diameter is 185 μm film spinning solution and in
The spray volume of liquid in sky.
Resulting hollow fiber separating film group is entered to blood processor to be molded, composition effective area 1.5m2's
Component.PMC3A obtained above (Mn 31000, Mw/Mn 2.5) 0.1g is then dissolved in the ethanol 40g/ water 60g aqueous solution
In (100g), coating fluid is made.Vertical to hold assembled component, portion is circulated coating fluid with flow velocity 100ml/ minutes from it,
Separation membrane surface is set to be contacted with coating fluid.
After coating fluid contact, the coating fluid in component is blown away with 0.1KMpa air, group is put into vacuum drier
Part, it is dried in vacuo 15 hours at 35 DEG C.
The blood processor obtained for the time point implements Hemocompatibility Tests, and (lactic dehydrogenase (LDH) activity is commented
Valency), as a result LDH activity is 0.5.
Implement γ ray sterilization under air atmosphere, under 25Kgy for same blood processor, for resulting blood
Liquid processor implement Hemocompatibility Tests, as a result LDH activity be 0.6, residual red root number be 0.Understand under air, dry
Radiation sterilizing is carried out under state, blood compatibility also hardly reduces.
Infrared ATR measure is carried out for the sample.Its infrared absorption curve is as shown in Figure 6.
Confirm the infrared absorption (1735cm from PMC3A-1Near) ester group (- O-C=O) peak.
In addition, infrared absorption (1735cm-1Near) peak intensity area P1 and infrared absorption (1595cm-1Near) peak intensity
The ratio between area P2 P1/P2 is 0.084.
Thermal cracking gas chromatography mass spectral analysis is carried out for the sample.
Its result is as shown in Figure 8.In addition, as control, thermal cracking gas chromatography mass spectrum is carried out only for PMC3A polymer
It is as shown in Figure 7 to analyze obtained result.
The peak of the chromatogram of PMC3A hot lysate is in RT3.2 minutes nearby (Fig. 7), and same vestige is in the examination
Sample is also found (Fig. 8).Then from mass spectrographic retrieval result (Fig. 9), the peak is the peak of trimethylene monomethyl ether.
Think that (pendant moiety) hot lysate that trimethylene monomethyl ether is PMC3A hydrolyzes what is formed, thus it is confirmed that,
PMC3A be present in the separation membrane surface of embodiment 11.
It should be noted that (comparative example 1) is recorded hereinafter, for no coating PMC3A seperation film similarly
Thermal cracking gas chromatography mass spectral analysis is carried out, the vestige at peak is not as a result found in RT3.2 minutes.
Implement the measure of contact angle for the sample.
Its result is as shown in following table.
Contact angle is 60 ° or so, even if repeated priming fills, contact angle is also without discovery change.
[table 6]
| Start filling number | 1 | 2 | 3 | 4 | 5 |
| Contact angle ° | 61 | 60 | 60 | 59 | 60 |
For the sample, UFR (ml/HrmmHg) is determined, as a result UFR=470 (ml/HrmmHg).
(embodiment 12~16)
Hollow fiber separating film is manufactured similarly to Example 11, its group is entered to blood processor to be molded, and is formed
Effective area 1.5m2Component.
Then, the species of the PMC3A concentration of coating fluid, the mixing ratio of water and organic solvent (ethanol) or organic solvent such as with
Under table change like that, in addition make blood processor similarly to Example 11, it is measure LDH activity, residual red root number, red
Outer absworption peak ratio.
As a result as shown in following table.
Also less change even if the increase of PMC3A concentration, LDH activity, do not find big difference.
On the other hand, if mixed solvent ratio (ETOH/H2O) amount that change then has organic solvent increases, therewith, peak ratio
(P1/P2) reduce, i.e. the tendency of the PMC3A of separation membrane surface amount reduction, be additionally present of LDH activity increase, i.e. blood
The tendency that compatibility reduces.But in the range of LDH activity is all in value possessed by usual commercially available product.
[table 7]
ETOH:Ethanol
MTOH:Methanol
(embodiment 17,18)
On being film-made spinning solution, relative to dimethyl acetamide (KISHIDA CHEMICAL Co., Ltd.s system, reagent
It is superfine) amount and PVP (BASF SE systems, K- of the polysulfones (Solvay S.A. systems, P-1700) of 79 mass parts
90) amount changes as shown in following table, in addition manufactures hollow fiber separating film similarly to Example 11, and group enters to blood
Liquid processor, PMC3A is coated with, determines LDH activity.
As a result as shown in following table.Formed even if change film stoste, LDH activity is also small, blood compatibility is good.
[table 8]
(embodiment 19)
Hollow fiber separating film is manufactured similarly to Example 11, its group is entered to blood processor to be molded, and is formed
Effective area 1.5m2Component.
Then by PMC4A obtained above (poly- [acrylic acid 4- methoxybutyls]) (Mn 29000, Mw/Mn 2.2) 0.1g
It is dissolved in the ethanol 40g/ water 60g aqueous solution (100g), makes coating fluid.Assembled component is vertically held, from it portion
Circulated coating fluid with flow velocity 100ml/ minutes, separation membrane surface is contacted with coating fluid.
After coating fluid contact, the coating fluid in component is blown away with 0.1KMpa air, group is put into vacuum drier
Part, it is dried in vacuo 15 hours at 35 DEG C, implements γ ray sterilization under air atmosphere, under 25Kgy, obtain blood processor.
Implement Hemocompatibility Tests for resulting blood processor, as a result LDH activity be 1.1, residual red root number be
0。
Parsed from ATR, P1/P2 ratios are 0.069.
(embodiment 20)
Hollow fiber separating film is manufactured similarly to Example 11, its group is entered to blood processor to be molded, and is formed
Effective area 1.5m2Component.
PMC5A obtained above (Mn 50000, Mw/Mn 2.3) 0.1g is then dissolved in ethanol 45g/ water 55g water
In solution (100g), coating fluid is made.Vertical to hold assembled component, portion is circulated coating with flow velocity 100ml/ minutes from it
Liquid, separation membrane surface is set to be contacted with coating fluid.
After coating fluid contact, the coating fluid in component is blown away with 0.1KMpa air, group is put into vacuum drier
Part, it is dried in vacuo 15 hours at 35 DEG C, implements γ ray sterilization under air atmosphere, under 25Kgy, obtain blood processor.
Implement Hemocompatibility Tests for resulting blood processor, as a result LDH activity be 1.5, residual red root number be
0。
Parsed from ATR, P1/P2 ratios are 0.071.
(embodiment 21)
Hollow fiber separating film is manufactured similarly to Example 11, its group is entered to blood processor to be molded, and is formed
Effective area 1.5m2Component.
PMC6A obtained above (Mn 29000, Mw/Mn 2.5) 0.1g is then dissolved in ethanol 45g/ water 55g water
In solution (100g), coating fluid is made.Vertical to hold assembled component, portion is circulated coating with flow velocity 100ml/ minutes from it
Liquid, separation membrane surface is set to be contacted with coating fluid.
After coating fluid contact, the coating fluid in component is blown away with 0.1KMpa air, group is put into vacuum drier
Part, it is dried in vacuo 15 hours at 35 DEG C, implements γ ray sterilization under air atmosphere, under 25Kgy, obtain blood processor.
Implement Hemocompatibility Tests for resulting blood processor, as a result LDH activity be 1.9, residual red root number be
0。
Parsed from ATR, P1/P2 ratios are 0.068.
(comparative example 1)
Seperation film does not contact coating fluid, and effective area 1.5m is in addition formed in the same manner as embodiment 1, embodiment 112
Component.To this implementation Hemocompatibility Tests, as a result LDH activity be 100, residual red root number be 6.It should be noted that radiation
LDH activity before line sterilizing is 10, it is known that compared with Example 1, the reduction of blood compatibility is big.
Infrared ATR measure is carried out for the sample, in its absorption curve, does not find infrared absorption (1735cm-1Near)
Peak.
For the sample carry out thermal cracking gas chromatography mass spectral analysis, but 2- (2- ethoxy ethoxies) ethanol or
PMC3A (poly- [acrylic acid 3- methoxyl groups propyl ester]) not can confirm that.
The measure of contact angle is carried out similarly to Example 1.As a result as shown in following table.Contact angle is 70 ° or so, i.e.,
Fill repeated priming, contact angle is also without discovery change.
[table 9]
| Start filling number | 1 | 2 | 3 | 4 | 5 |
| Contact angle ° | 69 | 72 | 70 | 70 | 71 |
Result above, which collects, is shown in following table.
[table 10]
LDH activity value, peak ratio are the value after sterilizing (25Kgy)
(comparative example 2)
PVP is added without in spinning solution is film-made, in addition manufacture point similarly to Example 1
From film, its group is entered to blood processor, is molded similarly to Example 1, implement blood phase for the component for being coated with PEt2A
Compatibility test, as a result LDH activity be 25, residual red root number be 3.
In addition, for the Specimen Determination contact angle.As a result as shown in following table.Contact angle due to repeated priming fill and
Change to hydrophobicity.Think that immobilizations of the PEt2A to separation membrane surface is unstable.
[table 11]
| Start filling number | 1 | 2 | 3 | 4 | 5 |
| Contact angle ° | 60 | 62 | 66 | 70 | 72 |
(comparative example 3)
PVP is added without in spinning solution is film-made, in addition manufacture point similarly to Example 11
From film, its group is entered to blood processor, is molded similarly to Example 11, implement blood for the component for being coated with PMC3A
Compatibility test, as a result LDH activity be 35, residual red root number be 1.
In addition, for the Specimen Determination contact angle, as a result contact angle changes because repeated priming fills to hydrophobicity.Recognize
For this is because, the adhesive strength between PMC3A and seperation film (independent polysulfones) is insufficient, PMC3A overlay films are in separation membrane surface
Existence it is unstable.
(comparative example 4)
Similarly implement blood for the commercially available product CX-21U (Toray Industries, Inc. system) for not meeting the present invention
Compatibility test, determine LDH activity and residual red root number, as a result the LDH activity be 66.2, residual red root number be 4.
Produce residual blood and think that blood compatibility is deteriorated.
It should be noted that here, as the hollow-fibre membrane for LDH activity measure, selection does not contain the residual trace of blood
Hollow-fibre membrane.
<Protein attachment evaluation test>
(embodiment 22)
Manufacture hollow fiber separating film similarly to Example 11, with the seperation film that is gathered formed effective length 15cm,
The area of film inner surface is 5 × 10-3m2Mode both ends are entered with epoxy (Bond Quickset, Konishi Co., Ltd.)
Row processing, makes 2 hollow fiber type blood processors.
The hollow fiber type blood processor is vertically held, makes manufactured PMC3A coating fluids similarly to Example 11
(PMC3A (Mn 31000, Mw/Mn 2.5) 0.1g, which is dissolved in the ethanol 40g/ water 60g aqueous solution (100g), to be formed) and with reality
Applying example 1, similarly (PEt2A (Mn 11600, Mw/Mn 3.9) 0.1g is dissolved in ethanol 35g/ water 65g to manufactured PEt2A coating fluids
The aqueous solution (100g) in form) circulated coating fluid from the top of hollow fiber type blood processor with flow velocity 1ml/ minutes respectively
20ml, separation membrane surface is set to be contacted with coating fluid.After coating fluid contact, hollow fiber type blood is blown away with 0.1KMpa air
Coating fluid in processor, hollow fiber type blood processor is put into vacuum drier, it is small that 15 are dried in vacuo at 35 DEG C
When.
Then γ ray sterilization is implemented under air atmosphere, under 25Kgy for hollow fiber type blood processor, for institute
Obtained hollow fiber type blood processor carries out (6-2) and has used the blood compatibility of inflammatory model blood to evaluate.
And then the blood that model blood is replaced by Healthy People carries out same evaluation.
As a result as shown in following table, the doughnut point after the blood compatibility evaluation of inflammatory model blood has been used
From film surface state photo as shown in Figure 10 and 11.
(comparative example 5)
Manufacture hollow fiber separating film similarly to Example 22, with the seperation film that is gathered formed effective length 15cm,
The area of film inner surface is 5 × 10-3m2Mode both ends are entered with epoxy (Bond Quickset, Konishi Co., Ltd.)
Row processing, makes hollow fiber type blood processor.
Sodium pyrosulfite 5g, sodium carbonate 1.75g are mixed in 7.2 liters of pure water, stir within 1 hour, makes oxidation resistance liquid.
Made oxidation resistance liquid is filled in above-mentioned hollow fiber type blood processor, sealing plug, under air atmosphere,
Implement γ ray sterilization under 25Kgy, carried out similarly to Example 22 for so obtained hollow fiber type blood processor
The protein attachment of inflammatory model blood and healthy human blood has been used to test.
Its result has used the doughnut after the blood compatibility evaluation of inflammatory model blood as shown in following table
The photo of the surface state of seperation film is as shown in figure 12.
In addition, implementing Hemocompatibility Tests similarly for the blood processor, (lactic dehydrogenase (LDH) activity is commented
Valency), as a result LDH activity is 10.5.
[table 12]
The hollow fiber type blood processor of embodiment 22 is any one in using healthy human blood, inflammatory model blood
In the case of kind, protein attachment amount is all few compared with comparative example 5, result, it is believed that in the case of such as dialysis treatment,
The generation of residual blood during treatment etc. is reduced.
In addition, for used inflammatory model blood blood compatibility evaluate after hollow fiber separating film surface
State is observed, all special without confirming in the case of using any one in PMC3A, PEt2A as a result in embodiment 22
Not obvious attachment (Figure 10 and Figure 11), in comparative example 5, fibrinous attachment (Figure 12) is found on its surface.
Industrial applicability
Think that the blood treatment seperation film of the present invention and group enter the blood processor of the film under air, drying
In the case of carrying out radiation sterilizing under state, very good blood compatibility, and even if long-term use of, blood are also shown
The reduction of liquid phase capacitive is also few, can be suitably used for haemodialysis, blood filtration, blood filtration dialysis, blood constituent fractionation,
The extracorporal circulatory system therapies such as oxygen assigns and blood plasma separates.
Japanese patent application (the Japanese Patent Application 2015- that the application is applied based on June 23rd, 2015 in Patent Office of Japan
And Japanese patent application (the Japanese Patent Application 2016- that applies in Patent Office of Japan on April 6th, 2,016 125420)
076397), introduced its content as reference in this.
Claims (15)
1. a kind of blood treatment seperation film, it has：
Seperation film containing polysulfones system macromolecule and PVP；With
It is arranged at least a portion on the surface of the seperation film and comprising the macromolecule material with structure shown in following formulas (1)
The overlay film of material,
In formula (1), R1It is hydrogen atom or methyl, R2It is methyl or ethyl, n is that 2~6, m is that 1~3, P represents repeat number, one point
Multiple R in son1、R2, n and m each can be the same or different.
2. blood treatment seperation film according to claim 1, wherein, the high score with structure shown in the formula (1)
The number-average molecular weight of sub- material is 8000~300000.
3. blood treatment seperation film according to claim 1 or 2, wherein, ATR-FTIR absorption is being implemented to surface
In infrared absorption curve when determining (ATR-IR), 1735cm-1The peak intensity P1 and 1595cm of neighbouring infrared absorption peak-1's
The ratio between the peak intensity P2 of infrared absorption peak P1/P2 is more than 0.015.
4. according to blood treatment seperation film according to any one of claims 1 to 3, wherein, R in formula (1)1Be hydrogen atom,
R2It is that ethyl, n are that 2, m is 2.
5. according to blood treatment seperation film according to any one of claims 1 to 3, wherein, R in formula (1)1It is methyl, R2
It is that methyl, n are that 2, m is 2.
6. according to blood treatment seperation film according to any one of claims 1 to 3, wherein, R in formula (1)1It is methyl, R2
It is that ethyl, n are that 2, m is 2.
7. according to blood treatment seperation film according to any one of claims 1 to 3, wherein, R in formula (1)1Be hydrogen atom,
R2It is that methyl, n are that 3, m is 1.
8. according to blood treatment seperation film according to any one of claims 1 to 3, wherein, R in formula (1)1Be hydrogen atom,
R2It is that methyl, n are that 4, m is 1.
9. according to blood treatment seperation film according to any one of claims 1 to 3, wherein, R in formula (1)1Be hydrogen atom,
R2It is that methyl, n are that 5, m is 1.
10. according to blood treatment seperation film according to any one of claims 1 to 3, wherein, R in formula (1)1It is hydrogen original
Son, R2It is that methyl, n are that 6, m is 1.
11. a kind of blood processor, it includes blood treatment seperation film according to any one of claims 1 to 10.
12. a kind of manufacture method of blood treatment seperation film, it has：
The process for manufacturing the seperation film containing polysulfones system macromolecule and PVP；With
At least a portion coating on the surface of the seperation film contains the painting with the high polymer material of structure shown in formula (1)
The process of cloth liquid.
13. the manufacture method of blood treatment seperation film according to claim 12, wherein, the coating fluid contain water and
Organic solvent, the organic solvent are ethanol, methanol or its mixture.
14. the manufacture method of the blood treatment seperation film according to claim 12 or 13, wherein,
In the process for manufacturing the seperation film,
Seperation film uses to be film-made containing the film stoste of polysulfones system macromolecule and PVP, in the film stoste
PVP is 27 matter relative to the high molecular ratio of polysulfones system (PVP/polysulfones system macromolecule)
Measure below %.
15. a kind of manufacture method of blood processor, it is the manufacture method of the blood processor described in claim 11, its according to
It is secondary to have：
The process for manufacturing the seperation film containing polysulfones system macromolecule and PVP；
The process being packaged to seal the inner space of the seperation film and outer space；With
Contain the high polymer material with structure shown in formula (1) on the surface of the seperation film and the coating of the surface of the encapsulation
Coating fluid process.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015-125420 | 2015-06-23 | ||
| JP2015125420 | 2015-06-23 | ||
| JP2016076397 | 2016-04-06 | ||
| JP2016-076397 | 2016-04-06 | ||
| PCT/JP2016/068571 WO2016208642A1 (en) | 2015-06-23 | 2016-06-22 | Separation membrane for blood treatment, and blood treatment device incorporating separation membrane |
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| CN107735167A true CN107735167A (en) | 2018-02-23 |
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| CN201680036377.XA Pending CN107735167A (en) | 2015-06-23 | 2016-06-22 | Blood treatment seperation film and group enter the blood processor of the film |
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| Country | Link |
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| US (1) | US20180185793A1 (en) |
| EP (1) | EP3315190A4 (en) |
| JP (1) | JPWO2016208642A1 (en) |
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| JP6327543B1 (en) * | 2017-07-13 | 2018-05-23 | 東洋紡株式会社 | Hollow fiber membrane having anti-inflammatory properties and method for producing the same |
| EP3655139A1 (en) * | 2017-07-17 | 2020-05-27 | Boehringer Ingelheim Vetmedica GmbH | Modified filter membrane and the use thereof |
| JPWO2020158451A1 (en) * | 2019-01-29 | 2020-08-06 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101068582A (en) * | 2004-10-15 | 2007-11-07 | 尼普洛株式会社 | Blood purification device and blood purification device package |
| CN101069823A (en) * | 2007-03-21 | 2007-11-14 | 清华大学 | Separation film for separating methanol/methyl-carbonate azotrope |
| CN101406813A (en) * | 2008-11-20 | 2009-04-15 | 天津大学 | Method for producing polysulfones hybrid membrane with separated pore passages formed by LUM particles |
| CN102015081A (en) * | 2008-03-31 | 2011-04-13 | 东丽株式会社 | Separation membrane, method of producing the same and separation membrane module using the separation membrane |
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| JPH0675667B2 (en) * | 1985-04-17 | 1994-09-28 | 東レ株式会社 | Method for producing semi-permeable membrane of polysulfone resin |
| JP3459836B2 (en) * | 1992-03-18 | 2003-10-27 | テルモ株式会社 | Platelet purification filter |
| JP3908839B2 (en) * | 1997-10-09 | 2007-04-25 | テルモ株式会社 | Hollow fiber membrane external blood perfusion oxygenator |
| WO2004087228A1 (en) * | 2003-03-28 | 2004-10-14 | Japan Science And Technology Agency | Polymers exhibiting both biocompatibility and temperature response |
| KR102230435B1 (en) * | 2013-09-30 | 2021-03-22 | 도레이 카부시키가이샤 | Porous membrane, blood purifying module incorporating porous membrane, and method for producing porous membrane |
| JP6737565B2 (en) * | 2014-10-17 | 2020-08-12 | 旭化成メディカル株式会社 | Separation membrane for blood treatment and blood treatment device incorporating the membrane |
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2016
- 2016-06-22 EP EP16814412.9A patent/EP3315190A4/en not_active Withdrawn
- 2016-06-22 WO PCT/JP2016/068571 patent/WO2016208642A1/en unknown
- 2016-06-22 US US15/738,813 patent/US20180185793A1/en not_active Abandoned
- 2016-06-22 CN CN201680036377.XA patent/CN107735167A/en active Pending
- 2016-06-22 JP JP2017524954A patent/JPWO2016208642A1/en active Pending
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|---|---|---|---|---|
| CN101068582A (en) * | 2004-10-15 | 2007-11-07 | 尼普洛株式会社 | Blood purification device and blood purification device package |
| CN101069823A (en) * | 2007-03-21 | 2007-11-14 | 清华大学 | Separation film for separating methanol/methyl-carbonate azotrope |
| CN102015081A (en) * | 2008-03-31 | 2011-04-13 | 东丽株式会社 | Separation membrane, method of producing the same and separation membrane module using the separation membrane |
| CN101406813A (en) * | 2008-11-20 | 2009-04-15 | 天津大学 | Method for producing polysulfones hybrid membrane with separated pore passages formed by LUM particles |
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Also Published As
| Publication number | Publication date |
|---|---|
| US20180185793A1 (en) | 2018-07-05 |
| EP3315190A1 (en) | 2018-05-02 |
| EP3315190A4 (en) | 2018-05-02 |
| WO2016208642A1 (en) | 2016-12-29 |
| JPWO2016208642A1 (en) | 2018-04-26 |
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